The invention relates to a process for the preparation of enantiomerically pure cycloalkano-indolecarboxylic acids and azaindolecarboxylic acids and pyrimido[1,2a]indolecarboxylic acids and their activated derivatives, which represent important intermediates for the synthesis of antiatherosclerotically active cycloalkanoindole derivatives and azaindole derivatives and pyrimido[1,2a]indole derivatives.
It is known that enantiomerically pure cycloalkano-indolecarboxylic acids and azaindole-carboxylic acids and their activated derivatives can be separated into the corresponding enantiomers by diastereomeric separation by conventional methods, for example by chromatography or fractional crystallization.
This process has a number of disadvantages: both the chromatographic diastereomeric separation and the fractional crystallization of the diastereomers are associated with high equipment requirements. In addition, in this case, generally 50% of the xe2x80x9cwrongxe2x80x9d diastereomer arises, which can no longer be recycled to the original preparation process.
This 50% loss of yield considerably impairs the economic efficiency of a (large) industrial-scale process, quite apart from the fact that 50% of xe2x80x9cby-productxe2x80x9d must be disposed of. Furthermore, the customary chiral auxiliary reagents are generally very expensive even in small amounts and can then usually only be prepared via a complex synthetic pathway.
It has now been found that enantiomerically pure cycloalkano-indolecarboxylic acids and azaindolecarboxylic acids and pyrimido[1,2a]indole-carboxylic acids and their activated derivates of the general formula (I) 
in which
A represents a radical of the formula 
xe2x80x83or 
J, D, E, G, L and M are identical or different and denote hydrogen, halogen, trifluoromethyl, carboxyl, hydroxyl, linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or linear or branched alkyl having up to 6 carbon atoms, which itself can be substituted by hydroxyl or by linear or branched alkoxy having up to 4 carbon atoms,
in which
R1 and R2, including the double bond linking them, together form a phenyl ring or pyridyl ring or a ring of the formula 
xe2x80x83where
R5 denotes hydrogen or linear or branched alkyl having up to 4 carbon atoms,
R3 and R4, including the double bond linking them, together form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical, where all the ring systems listed under R1/R2 and R3/R4 are optionally up to trisubstituted identically or differently by halogen, trifluoromethyl, carboxyl, hydroxyl, by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or by linear or branched alkyl having up to 6 carbon atoms, which itself can be substituted by hydroxyl or by linear or branched alkoxy having up to 4 carbon atoms,
T represents cycloalkyl having 4 to 12 carbon atoms, or represents linear or branched alkyl having up to 12 carbon atoms,
Q represents hydroxyl or an activating radical,
and their salts are obtained
by firstly converting compounds of the general formula (II), 
in which
R6 together with the oxygen atom represents a chiral alcohol radical, by means of compounds of the general formula (III)
Txe2x80x94Zxe2x80x83xe2x80x83(III)
xe2x80x83in which
T has the meaning specified and
Z represents a typical leaving group, such as bromine, chlorine, iodine, mesyl, tosyl, or trifluoromethylsulphonyl, preferably iodine or bromine,
n inert solvents in the presence of a base by diastereoselective alkylation into the enantiomerically pure compounds of the general formula (IV) 
in which
T and R6 have the meaning specified,
then converting these, by halogenation, into the enantiomerically pure compounds of the general formula (V) 
in which
T and R6 have the meaning specified
and
R7 represents halogen, such as chlorine, bromine, iodine, preferably bromine, reacting these in a further step with compounds of the general formula (VI)
Axe2x80x94Hxe2x80x83xe2x80x83(VI)
in which
R1, R2, R3 and R4 have the meaning specified,
to give the enantiomerically pure compounds of the general formula (VII) 
in which
A, T and R6 have the meaning specified,
and, in the case of compounds of the general formula (I) where Qxe2x95x90OH, carrying out a hydrolysis, and in the case where Q=activating radical, starting from the enantiomerically pure acids reacting with activating reagents.
These can be reacted in a further step with D- or L-phenylglycinol to give compounds of the general formula (VIII) 
where these are in this case active compounds for medicaments.
The process according to the invention can be described by way of example by the following formula diagram: 
Surprisingly, the process according to the invention gives the wanted enantiomerically pure cycloalkano-indolecarboxylic acids and azaindole-carboxylic acids and pyrimido-indolecarboxylic acids and their activated derivatives without great equipment requirements in very good yields and high purity.
Depending on the configuration of the radical R6 and stearic effects of the alkyl halide (II) used, the alkylation of the compound (II) proceeds in high yields and in a simple manner diastereoselectively for the first time. The compounds (IV) arise with high diastereomeric excess and crystallize out of the reaction mixture directly, as a result of which even the simple crystallization of crude products gives the compounds of the formula (IV) in diastereomerically pure form.
A further advantage of the process according to the invention is that, by suitable choice of the solvent and a base, the unwanted diastereomer can be epimerized to the desired diastereomer, which in turn crystallizes out directly. Thus, further (wanted) diastereomerically pure product can be produced from the mother liquors by repeated epimerization and crystallization. Direct addition of the mother liquors to the alkylation step can optimize the entire process in the form of a cyclic process.
A further advantage of the process according to the invention is that the halogenated compounds of the general formula (V) surprisingly react with the compounds of the general formula (VI) without racemization at the carbon atom in the 2 position to the carboxylic acid function, to give the compounds of the general formula (VII).
A further advantage of the process according to the invention is the racemization-free reaction at the carbon atom at the 2 position to the carboxylic acid function of the compounds of the general formula (I) where Q=activated radical, preferably chlorine, to give the compounds of the general formula (VIII).
Furthermore, it is a great advantage of the process according to the invention that the starting compounds are very readily accessible. They may be prepared in good yields from relatively simple building blocks with low equipment requirements. Furthermore, the process according to the invention enables amounts of known racemates of the compounds of the general formula (I) present to be converted into the corresponding enantiomers. The process according to the invention enables the preparation of the compounds according to the invention of the general formula (I) using few synthetic stages and in a considerably higher overall yield than by processes known from the prior art.
R6, in the context of the above specified definition, represents a chiral alcohol radical, such as (+)- or (xe2x88x92)-menthyl, (+)- or (xe2x88x92)-bornyl, (+)- or (xe2x88x92)-isobornyl or (xe2x88x92)-8-phenylmenthyl. Preferably, R9 represents (+)- or (xe2x88x92)-menthyl.
Activating radicals (Q), in the context of the invention, generally represent chloride, bromide, mesylate, tosylate or trifluoride. Preference is given to chloride. Preferably, by the process according to the invention, compounds of the general formula (I) are prepared, in which
A represents a radical of the formula 
in which
J, D, E, G, L and M are identical or different and denote hydrogen, fluorine, chlorine, bromine trifluoromethyl, carboxyl, hydroxyl, linear or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or linear or branched alkyl having up to 4 carbon atoms which itself can be substituted by hydroxyl or by linear or branched alkoxy having up to 3 carbon atoms, R1 and R2, including the double bond linking them, together form a phenyl ring or pyridyl ring or a ring of the formula 
xe2x80x83in which
R5 denotes hydrogen or linear or branched alkyl having up to 3 carbon atoms,
R3 and R4, including the double bond linking them, together form a phenyl ring or a cyclopentene, cyclohexene, cycloheptene, cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene or oxocyclooctene radical,
xe2x80x83where all ring systems, listed under R1/R2 and R3/R4 are optionally up to disubstituted identically or differently by fluorine, chlorine, bromine, trifluoromethyl, carboxyl, hydroxyl, by linear or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or by linear or branched alkyl having up to 4 carbon atoms, which itself can be substituted by hydroxyl or by linear or branched alkoxy having up to 3 carbon atoms,
T represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or represents linear or branched alkyl having up to 10 carbon atoms,
Q represents hydroxyl or represents an activating radical,
and their salts.
Particularly preferably, compounds of the general formula (I) are prepared by the process according to the invention in which
A represents a radical of the formula 
in which
J, D, E, G, L and M are identical or different and denote hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl, hydroxyl, linear or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or denote linear or branched alkyl having up to 3 carbon atoms,
R1 and R2, including the double bond linking them, together form a phenyl ring or pyridyl ring or a ring of the formula 
xe2x80x83in which
R5 denotes hydrogen or methyl,
R3 and R4, including the double bond linking them, together form a phenyl ring or a cyclopentene, cyclohexene, cycloheptene, cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene or oxocyclooctene radical,
where all ring systems listed under R1/R2 and R3/R4 are optionally up to disubstituted identically or differently by fluorine, chlorine, bromine, trifluoromethyl, carboxyl, hydroxyl, by linear or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by linear or branched alkyl having up to 4 carbon atoms which itself can by substituted by hydroxyl, methoxy or ethoxy.
T represents cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or linear or branched alkyl having up to 6 carbon atoms,
Q represents hydroxyl or an activating radical,
and their salts.
Very particularly preferably, the compounds of the general formula (I), in which
A represents a radical of the formula 
xe2x80x83in which
R3 and R4=phenyl ring
and having the radical *CHxe2x80x94Txe2x80x94COQ in the paraposition and Q=chlorine, and their salts,
are prepared by the above described process.
Suitable solvents for the alkylation of the compound of the general formula (II) are customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloro-methane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane, methanol or ethanol. It is equally possible to use mixtures of the said solvents. Preference is given to dimethylformamide.
The alkylation is carried out in the solvents listed above, if appropriate under a protective gas atmosphere, at temperatures of xe2x88x9220xc2x0 C. to +100xc2x0 C., preferably at xe2x88x9210xc2x0 C. to +30xc2x0 C., at atmospheric pressure.
Suitable bases for the diastereoselective alkylation are the customary basic compounds. These include alkali metal hydrides, such as sodium hydride, alkyli metal amides such as sodium amide, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, or organic amines, such as trialkylamines, e.g. triethylamine, or organolithium compounds, such as butyllithium or phenyllithium. Preference is given to potassium tert-butoxide.
In the diastereoselective alkylation, the base is used in an amount from 1 mol to 10 mol, preferably from 1.2 mol to 3 mol, based on 1 mol of the compounds of the general formula (II).
Suitable solvents for the halogenation of the compound for the general formula (IV) are customary solvents which do not change under the reaction conditions. These preferably include tetrachloromethane, chlorobenzene, dichlorobenzene, acetonitrile, acetic acid, sulphuric acid, nitrobenzene, 1,2-dichloroethane, dichloromethane, trichloromethane.
For the halogenation, customary halogenating agents are suitable, such as bromine, chlorine, NBS, NCS, dichlorodimethylhydantoin, dibromodimethylhydantoin, trichlorisocyanuric acid, chloramine-T.
Suitable free-radical starters are, for example, AIBN, peroxides, such as dibenzoyl peroxide, t-butyl hydroperoxide, dilauryl peroxide, t-butyl peroxide, butyl perbenzoate, di-t-butyl peroxalate, and photochemical methods.
The halogenation is carried out in the solvents listed above, if appropriate under a protective gas atmosphere, at temperatures of 20xc2x0 C. to 180xc2x0 C., if appropriate under pressure. Preferably, the halogenation is carried out at 70xc2x0 C. to 130xc2x0 C.
In the halogenation, the halogenating agent is used at 0.8 mol to 1.7 mol of active halogen, based on 1 mol of the compounds of the general formula (I).
Suitable solvents for the alkylation of the compound of the general formula (VI) are customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, N-methylpyrrolidone, hexamethyl-phosphoric triamide, acetonitrile, acetone or nitromethane. It is equally possible to use mixtures of the said solvents. Preference is given to dimethylformamide, toluene and tetrahydrofuran.
The alkylation is carried out in the solvents listed above, if appropriate under a protective gas atmosphere, at temperatures of xe2x88x9220xc2x0 C. to +100xc2x0 C., preferably at xe2x88x9210xc2x0 C. to +30xc2x0 C., at atmospheric pressure.
Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as barium hydroxide, alkali metal carbonates and alkali metal hydrogen carbonates, such as sodium carbonate, sodium hydrogen carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal alkoxides or alkaline earth metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines (trialkyl(C1-C6) amines), such as triethylamine, or heterocylcles, such as 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperdine or morpholine. It is also possible to use alkali metals, such as sodium, or their hydrides, such as sodium hydride, as bases. Preference is given to sodium hydrogen carbonate, potassium carbonate and potassium tert-butoxide, DBU or DABCO.
In the alkylation, the base is used in an amount of 1 mol to 10 mol, preferably of 1.2 mol to 3 mol, based on 1 mol of the compounds of the general formula (II).
To eliminate the chiral radical R6 in the compounds of the general formula (VII), the customary organic carboxylic acids are suitable, such as acetic acid, formic acid, trifluoroacetic acid, methanesulphonic acid, or inorganic acids, such as hydrobromic acid, hydrochloric acid or sulphuric acid or mixtures of the said acids. Preference is given to acetic acid, formic acid, hydrobromic acid and/or sulphuric acid. Very particular preference is given to the mixture acetic acid/sulphuric acid and also formic acid/hydrobromic acid and formic acid/sulphuric acid.
The acids or their mixtures are simultaneously employed as solvent and thus used in a great excess.
The elimination proceeds in a temperature range from 0xc2x0 C. to +150xc2x0 C., preferably from 40xc2x0 C. to 100xc2x0 C.
It can generally be carried out at atmospheric pressure, but optionally alternatively at superatmospheric pressure or reduced pressure (e.g. 0.5 to 3 bar).
After neutralization with bases in water or in one of the solvents listed above, in particular in a water/toluene, water/isopropanol, water/methanol or water/ethanol mixture, the acids are worked up by a customary method.
Suitable bases for the neutralization are alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. Preference is given to sodium hydroxide.
Suitable solvents for the activation of the compounds of the general formula (I) are customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, acetonitrile, acetone or nitromethane. It is equally possible to use mixtures of the said solvents. Preference is given to dimethylformamide, toluene and dichloromethane.
For the activation, conventional activation agents are suitable, for example oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, trichloroisocyanuric acid, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, mesyl chloride, tosyl chloride, phosgene, trifluoromethanesulphonyl chloride, sulphuryl chloride. Preference is given to thionyl chloride, oxalyl chloride and phosgene.
The activation is carried out in the solvents listed above, if appropriate under a protective gas atmosphere, at temperatures of xe2x88x9220xc2x0 C. to 120xc2x0 C., optionally under pressure. Preferably, the activation is carried out at xe2x88x9220xc2x0 C. to 80xc2x0.
In the activation, the activation reagent is used in an amount of 1 mol to 10 mol, based on 1 mol of the compound of the general formula (I), or is optionally employed as solvent.
The activation is optionally performed with the addition of bases, such as organic amines (trialkyl(C1-C6)amines), such as triethylamine, or heterocycles, such as 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. If appropriate, the activated derivatives can be prepared starting from carboxylic salts of alkali metals and alkaline earth metals by reaction with, e.g., oxalyl chloride.
The compounds of the general formula (II), 
in which
R6 represents a chiral alcohol radical,
are obtained
by esterifying compounds of the general formula (IX) 
with chiral alcohols according to processes disclosed in the literature.
The compounds of the general formula (IX) are known per se or can be prepared by customary methods.
The enantiomerically pure compounds of the general formula (I) in which Q represents tert-butoxy are novel and can be prepared by first converting racemic carboxylic acids of the general formula (X) 
in which
T has the meaning specified above, by reaction with (R)- or (S)-phenylethylamine in inert solvents and subsequent crystallization of the phenethylammonium salts and subsequent hydrolysis of the salts, into the enantiomerically pure compounds of the general formula (XI) 
in which
T has the meaning specified above,
converting these in a further step with isobutene, in inert solvents and in the presence of acids, into the enantiomerically pure esters (XII) 
in which
T has the meaning specified above,
then converting the esters (XII) by halogenation into the enantiomerically pure compounds of the general formula (XIII) 
in which
T has the meaning specified above
and
R7 represents a typical leaving group, such as chlorine, bromine, iodine, tosylate or mesylate, preferably bromine,
in a further step, by reaction with compounds of the general formula (VI)
Axe2x80x94Hxe2x80x83xe2x80x83(VI)
in which
A has the meaning specified above,
preparing the enantiomerically pure compounds of the general formula (I) 
in which
A and T have the meaning specified above and
Q represents tert-butyl,
and in the case of the compounds of the general formula (I) where Qxe2x95x90OH, carrying out a hydrolysis.
Tert-butyl esters are generally saponified with acids, for example hydrochloric acid or trifluoroacetic acid, in the presence of one of the above specified solvents and/or water or their mixtures, preferably with dioxane or tetrahydrofuran.
The compounds of the general formula (X) are prepared from the corresponding esters disclosed in the literature by hydrolysis according to methods disclosed in the literature. 